We are examining the mechanism of cdk5 kinase activation and inhibition. The interaction of this kinase with its different activator proteins and fragments thereof produce complex effects on its biological activity. We have described a fragment (CIP) of the cdk5-activator protein, p35, that produces high-affinity inhibition of cdk5 by selective competition with the p25 activator protein. The p25 form of the cdk5 activator appears in neurons under stress, induces hyperphosphorylation of the microtubule associated protein, tau, and transfection with the inhibitor peptide can prevent this in neuronal cell culture assays (Zheng et al, 2005).[unreadable] [unreadable] We are engaged in studies to further define the mechanism of this selective inhibition. Cdk5 is a member of the cyclin-dependent kinase family. Although cdk5 activator proteins are not cyclins, the activator interfaces with the kinases in this family are largely similar and they induce similar conformational transitions. Thus we are also exploring computational means to obtain information about the interactions of CIP and related inhibitors with the cdk5 kinase.